Gene expression profiles of transcripts in amyloid precursor protein transgenic mice: up-regulation of mitochondrial metabolism and apoptotic genes is an early cellular change in Alzheimer's disease

Reddy, P. Hemachandra; McWeeney, Shannon K.; Park, Byung; Mańczak, Maria; Gutala, Ramana; Partovi, Dara; Jung, Youn-Sang; Yau, Vincent; Searles, Robert P.; Mori, Motomi; Quinn, Joseph F.

doi:10.1093/hmg/ddh140

Cited by 305 publications

(215 citation statements)

References 59 publications

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“…The up-regulation of mitochondria-and nuclear-encoded COX subunits found in AD patients and a transgenic model might represent a cellular attempt to compensate for the A␤-mediated reduction in COX activity (35). Therefore, our observations along with others mentioned above suggest that, in AD, COX deficiency would not be the cause for the accumulation of A␤ but, rather, a consequence of the accumulation of A␤.…”

Section: Discussionsupporting

confidence: 69%

Cytochrome c oxidase deficiency in neurons decreases both oxidative stress and amyloid formation in a mouse model of Alzheimer's disease

Fukui¹,

Díaz²,

Garcia³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

168

140

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Defects in the mitochondrial cytochrome c oxidase (COX) have been associated with Alzheimer's Disease, in which the agedependent accumulation of ␤-amyloid plays an important role in synaptic dysfunction and neurodegeneration. To test the possibility that age-dependent decline in the mitochondrial respiratory function, especially COX activity, may participate in the formation and accumulation of ␤-amyloid, we generated mice expressing mutant amyloid precursor protein and mutant presenilin 1 in a neuron-specific COX-deficient background. A neuron-specific COXdeficient mouse was generated by the Cre-loxP system, in which the COX10 gene was deleted by a CamKII␣ promoter-driven Crerecombinase. COX10 is a farnesyltransferase involved in the biosynthesis of heme a, required for COX assembly and function. These KO mice showed an age-dependent COX deficiency in the cerebral cortex and hippocampus. Surprisingly, COX10 KO mice exhibited significantly fewer amyloid plaques in their brains compared with the COX-competent transgenic mice. This reduction in amyloid plaques in the KO mouse was accompanied by a reduction in A␤42 level, ␤-secretase activity, and oxidative damage. Likewise, production of reactive oxygen species from cells with partial COX activity was not elevated. Collectively, our results suggest that, contrary to previous models, a defect in neuronal COX does not increase oxidative damage nor predispose for the formation of amyloidgenic amyloid precursor protein fragments. mitochondria ͉ oxidative phosphorylation ͉ neurodegeneration A lzheimer's disease (AD) is the most prevalent age-related neurodegenerative disease, characterized by progressive brain atrophy/neuronal death that results in cognitive and memory impairment. Starting from the identification of genes responsible for familial AD, which is now known to constitute only Ͻ5% of total AD incidence, an ''amyloid hypothesis'' has been built up during the past few decades, and an enormous effort has been devoted to understand the toxic mechanism of ␤-amyloid (A␤), which forms extracellular amyloid plaques and is generated by a successive proteolytic cleavage of amyloid precursor protein (APP) by ␤-secretase and a ␥-secretase complex containing presenilins (1). Although it is not clear to what extent different A␤ species (soluble oligomers, insoluble aggregates, extracellular species, or intracellular species) contribute to neurodegeneration in vivo, recent studies demonstrated the toxicity of diverse A␤ species in vitro, in situ, and in vivo, confirming the importance of age-dependent A␤ accumulation in AD pathogenesis (2-5).Recently, age-dependent accumulation of mutations in mitochondrial DNA (mtDNA) and resulting increase in oxidative stress and impairment in mitochondrial respiratory chain, especially complex IV or cytochrome c oxidase (COX), gained attention as potential factors that could participate in the onset of sporadic AD (6). A number of studies reported a reduction in COX activity and an increase in oxidative stress in brain tissues and plate...

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Section: Discussionsupporting

confidence: 69%

Cytochrome c oxidase deficiency in neurons decreases both oxidative stress and amyloid formation in a mouse model of Alzheimer's disease

Fukui¹,

Díaz²,

Garcia³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

168

140

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“…The correspondence of relatively greater activation in multiple right hemisphere regions with equivalent behavioral memory performances supports the notion of compensation through the employment of more bilateral network regions (see network view in Cabeza [9]). In all, support for the compensatory hypothesis has been demonstrated across a whole host of neuropsychological [2,10,27,41] and neuroimaging [3,4,6,22] investigations, as well as with neurochemical [13,17,35], neurotrophic [18], and mitochondrial DNA alterations [33].…”

Section: Resultsmentioning

confidence: 90%

Verbal paired-associate learning by APOE genotype in non-demented older adults: fMRI evidence of a right hemispheric compensatory response

Han

Houston

Jak

et al. 2007

Neurobiology of Aging

139

114

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Previous studies of episodic memory report a greater extent of blood-oxygenation-level-dependent (BOLD) response in non-demented older adults with the apolipoprotein E epsilon-4 (APOE ε4) allele than in those without the allele. We conducted a functional MRI study to investigate whether APOE genotype is related to brain response to verbal paired-associate encoding and consolidation, particularly in the right hemisphere, among non-demented older adults. Structurally segmented volumes and BOLD response were measured in 13 non-ε4 and 12 ε4 subjects. The ε4 group displayed greater activation than the non-ε4 group in multiple right hemisphere regions for previously encoded word pairs relative to fixation. Activation within manually outlined hippocampal regions of interest also displayed genotype-specific dissociations consistent with whole brain analyses. Furthermore, this differential BOLD response occurred in the presence of equivalent behavioral and neuropsychological performances as well as comparable hippocampal and overall structural segmentation volumes between groups. Results implicate a widely distributed and interconnected network of right hemisphere brain regions that may be involved in compensating for APOE ε4-related deficiencies associated with verbal episodic memory encoding and consolidation.

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“…Quantitative morphometric analysis of mitochondria shows increased abnormal and damaged mitochondria in AD (9,10). Multiple lines of evidence support APP and A␤ as contributing factors to mitochondrial dysfunction in AD: both APP and A␤ are present in mitochondrial membrane and interact with mitochondrial proteins, block mitochondrial import channels, impair mitochondrial transport, disrupt the electron transfer chain, increase ROS levels, and cause mitochondrial damage (11)(12)(13)(14)(15).…”

mentioning

confidence: 99%

Amyloid-β overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins

Wang

Siedlak

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

762

608

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Mitochondrial dysfunction is a prominent feature of Alzheimer disease but the underlying mechanism is unclear. In this study, we investigated the effect of amyloid precursor protein (APP) and amyloid ␤ on mitochondrial dynamics in neurons. Confocal and electron microscopic analysis demonstrated that Ϸ40% M17 cells overexpressing WT APP (APPwt M17 cells) and more than 80% M17 cells overexpressing APPswe mutant (APPswe M17 cells) displayed alterations in mitochondrial morphology and distribution. Specifically, mitochondria exhibited a fragmented structure and an abnormal distribution accumulating around the perinuclear area. These mitochondrial changes were abolished by treatment with ␤-site APP-cleaving enzyme inhibitor IV. From a functional perspective, APP overexpression affected mitochondria at multiple levels, including elevating reactive oxygen species levels, decreasing mitochondrial membrane potential, and reducing ATP production, and also caused neuronal dysfunction such as differentiation deficiency upon retinoic acid treatment. At the molecular level, levels of dynamin-like protein 1 and OPA1 were significantly decreased whereas levels of Fis1 were significantly increased in APPwt and APPswe M17 cells. Notably, overexpression of dynamin-like protein 1 in these cells rescued the abnormal mitochondrial distribution and differentiation deficiency, but failed to rescue mitochondrial fragmentation and functional parameters, whereas overexpression of OPA1 rescued mitochondrial fragmentation and functional parameters, but failed to restore normal mitochondrial distribution. Overexpression of APP or A␤-derived diffusible ligand treatment also led to mitochondrial fragmentation and reduced mitochondrial coverage in neuronal processes in differentiated primary hippocampal neurons. Based on these data, we concluded that APP, through amyloid ␤ production, causes an imbalance of mitochondrial fission/fusion that results in mitochondrial fragmentation and abnormal distribution, which contributes to mitochondrial and neuronal dysfunction.amyloid precursor protein ͉ DLP1 ͉ mitochondrial fragmentation ͉ OPA1 ͉ perinuclear accumulation

show abstract

Gene expression profiles of transcripts in amyloid precursor protein transgenic mice: up-regulation of mitochondrial metabolism and apoptotic genes is an early cellular change in Alzheimer's disease

Cited by 305 publications

References 59 publications

Cytochrome c oxidase deficiency in neurons decreases both oxidative stress and amyloid formation in a mouse model of Alzheimer's disease

Cytochrome c oxidase deficiency in neurons decreases both oxidative stress and amyloid formation in a mouse model of Alzheimer's disease

Verbal paired-associate learning by APOE genotype in non-demented older adults: fMRI evidence of a right hemispheric compensatory response

Amyloid-β overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins

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